The present invention relates to cardiac muscular control, in particular control using non-excitatory electrical signals.
The heart is a muscular pump whose mechanical activation is controlled by electrical stimulation generated at a right atrium and passed to the entire heart. In a normal heart, the electrical stimulation that drives the heart originates as action potentials in a group of pacemaker cells lying in a sino-atrial (SA) node in the right atrium. These action potentials then spread rapidly to both right and left atria. When the action potential reaches an unactivated muscle cell, the cell depolarizes (thereby continuing the spread of the action potential) and contracts. The action potentials then enter the heart""s conduction system and, after a short delay, spread through the left and right ventricles of the heart. It should be appreciated that activation signals are propagated within the heart by sequentially activating connected muscle fibers. Each cardiac muscle cell generates a new action potential for stimulating the next cell, after a short delay and in response to the activation signal which reaches it. Regular electrical currents can be conducted in the heart, using the electrolytic properties of the body fluids, however, due the relatively large resistance of the heart muscle, this conduction cannot be used to transmit the activation signal.
In a muscle cell of a cardiac ventricle, the resting potential across its cellular membrane is approximately xe2x88x9290 mV (millivolts) (the inside is negatively charged with respect to the outside). FIG. 1A shows a transmembrane action potential of a ventricle cardiac muscle cell during the cardiac cycle. When an activation signal reaches one end of the cell, a depolarization wave rapidly advances along the cellular membrane until the entire membrane is depolarized, usually to approximately +20 mV (23). Complete depolarization of the cell membrane occurs in a very short time, about a few millisecond. The cell then rapidly (not as rapid as the depolarization) depolarizes by about 10 mV. After the rapid depolarization, the cell slowly repolarizes by about 20 mV over a period of approximately 200-300 msec (milliseconds), called the plateau (25). It is during the plateau that the muscle contraction occurs. At the end of the plateau, the cell rapidly repolarizes (27) back to its resting potential (21). Different cardiac muscle cells have different electrical characteristics, in particular, cells in an SA node do not have a substantial plateau and do not reach as low a resting potential as ventricular cells.
In the following discussion, it should be appreciated that the exact mechanisms which govern action potentials and ionic pumps and channels are only partly known. Many theories exist and the field in is a constant state of flux.
The electrical activity mirrors chemical activity in a cell. Before depolarization (at resting), the concentration of sodium ions inside the cell is about one tenth the concentration in the interstitial fluid outside the cell. Potassium ions are about thirty-five times more concentrated inside the cell than outside. Calcium ions are over ten thousand times more concentrated outside the cell than inside the cell. These concentration differentials are maintained by the selective permeability of the membrane to different ions and by ionic pumps in the membrane of the cell which continuously pump sodium and calcium ions out and potassium ions in. One result of the concentration differences between the cell and the external environment is a large negative potential inside the cell, about 90 mV as indicated above.
When a portion of the cell membrane is depolarized, such as by an action potential, the depolarization wave spreads along the membrane. This wave causes a plurality of voltage-gated sodium channels to open. An influx of sodium through these channels rapidly changes the potential of the membrane from negative to positive (23 in FIG. 1A). Once the voltage becomes less negative, these channels begin to close, and do not open until the cell is again depolarized. It should be noted that the sodium channels must be at a negative voltage of at least a particular value in order to be primed for reopening. Thus, these channels cannot be opened by an activation potential before the cell has sufficiently repolarized. In most cells, the sodium channels usually close more gradually than they open. After the rapid depolarization, the membrane starts a fast repolarization process. The mechanism for the fast repolarization is not fully understood, although closing of the sodium channels appears to be an important factor. Following a short phase of rapid repolarization, a relatively long period (200-300 msec) of slow repolarization term the plateau stage (25 in FIG. 1A) occurs. During the plateau it is not believed to be possible to initiate another action potential in the cell, because the sodium channels are inactivated.
Two mechanisms appear to be largely responsible for the long duration of the plateau, an inward current of calcium ions and an outward current of potassium ions. Both currents flow with their concentration gradients, across the membrane. The net result is that the two types of current electrically subtract from each other. In general, the flow of potassium and calcium is many times slower than the flow of the sodium, which is the reason why the plateau lasts so long. According to some theories, the potassium channels may also open as a result of the action potential, however, the probability of a potassium channel opening is dependent on the potential. Thus, many channels open only after the depolarization of the cell is under way or completed. Possibly, at least some of the potassium channels are activated by the calcium ions. In addition, some of the potassium channels are triggered by the repolarization of the membrane. The membrane permeability to potassium gradually increases, following its drop during the rapid depolarization (23). The calcium channels also conduct sodium back into the cell, which helps extend the plateau duration.
The inward calcium current during the normal cardiac action potential contributes to the action potential plateau and is also involved in the contractions (directly and/or indirectly) in the cardiac muscle cells. In a process termed calcium induced calcium release, the inward current of calcium induces the release of calcium ions stored in intracellular calcium stores (probably the sacroplasmic reticulum). The existence and importance of a physical link between the reticulum and the calcium channels in cardiac muscle is unclear. However, the response curve of these calcium stores may be bell-shaped, so that too great an influx of calcium may reduce the amount of available calcium relative to amount made available by a smaller influx.
In single cells and in groups of cells, time is required for cells to recover partial and full excitability during the repolarization process. While the cell is repolarizing (25, 27 in FIG. 1A), it enters a state of hyper polarization, during which the cell cannot be stimulated again to fire a new action potential. This state is called the refractory period. The refractory period is divided into two parts. During an absolute refractory period, the cell cannot be re-excited by an outside stimulus, regardless of the voltage level of the stimulus. During a relative refractory period, a much larger than usual stimulus signal is required to cause the cell to fire a new action potential. The refractory state is probably caused by the sodium channels requiring priming by a negative voltage, so the cell membrane cannot depolarize by flow of sodium ions until it is sufficiently repolarized. Once the cell returns to its resting potential (21), the cell may be depolarized again.
In an experimental methodology called voltage clamping, an electrical potential is maintained across at least a portion of a cell membrane to study the effects of voltage on ionic channels, ionic pumps and on the reactivity of the cell.
It is known that by applying a positive potential across the membrane, a cell may be made more sensitive to a depolarization signal. Some cells in the heart, such as the cells in the SA node (the natural pacemaker of the heart) have a resting potential of about xe2x88x9255 mV. As a result, their voltage-gated sodium channels are permanently inactivated and the depolarization stage (23) is slower than in ventricular cells (in general, the action potential of an SA node cell is different from that shown in FIG. 1A). However, cells in the SA node have a built-in leakage current, which causes a self-depolarization of the cell on a periodic basis. In general, it appears that when the potential of a cell stay below about xe2x88x9260 mV for a few msec, the voltage-gated sodium channels are blocked. Applying a negative potential across its membrane make a cell less sensitive to depolarization and also hyperpolarizes the cell membrane, which seems to reduce conduction velocity.
In modern cardiology many parameters of the heart""s activation can be controlled. Pharmaceuticals can be used to control the conduction velocity, excitability, contractility and duration of the refractory periods in the heart. These pharmaceuticals may be used to treat arrhythmias and prevent fibrillations. A special kind of control can be achieved using a pacemaker. A pacemaker is an electronic device which is typically implanted to replace the heart""s electrical excitation system or to bypass a blocked portion of the conduction system. In some types of pacemaker implantation, portions of the heart""s conduction system, for example an atrial-ventricle (AV) node, must be ablated in order for the pacemaker to operate correctly.
Another type of cardiac electronic device is a defibrillator. As an end result of many diseases, the heart may become more susceptible to fibrillation, in which the activation of the heart is substantially random. A defibrillator senses this randomness and resets the heart by applying a high voltage impulse(s) to the heart.
Pharmaceuticals are generally limited in effectiveness in that they affect both healthy and diseased segments of the heart, usually, with a relatively low precision. Electronic pacemakers, are further limited in that they are invasive, generally require destruction of heart tissue and are not usually optimal in their effects. Defibrillators have substantially only one limitation. The act of defibrillation is very painful to the patient and traumatic to the heart.
xe2x80x9cElectrical Stimulation of Cardiac Myoctes,xe2x80x9d by Ravi Ranjan and Nitish V. Thakor, in Annals of Biomedical Engineering, Vol. 23, pp. 812-821, published by the Biomedical Engineering Society, 1995, the disclosure of which is incorporated herein by reference, describes several experiments in applying electric fields to cardiac muscle cells. These experiments were performed to test theories relating to electrical defibrillation, where each cell is exposed to different strengths and different relative orientations of electric fields. One result of these experiments was the discovery that if a defibrillation shock is applied during repolarization, the repolarization time is extended. In addition, it was reported that cells have a preferred polarization. Cardiac muscle cells tend to be more irregular at one end than at the other. It is theorized, in the article, that local xe2x80x9chot spotsxe2x80x9d of high electrical fields are generated at these irregularities and that these xe2x80x9chot spotsxe2x80x9d are the sites of initial depolarization within the cell, since it is at these sites that the threshold for depolarization is first reached. This theory also explains another result, namely that cells are more sensitive to electric fields in their longitudinal direction than in their transverse direction, since the irregularities are concentrated at the cell ends. In addition, the asymmetric irregularity of the cells may explain results which showed a preferred polarity of the applied electric field.
The electrical activation of skeleton muscle cells is similar to that of cardiac cells in that a depolarization event induces contraction of muscle fibers. However, skeleton muscle is divided into isolated muscle bundles, each of which is individually enervated by action potential generating nerve cells. Thus, the effect of an action potential is local, while in a cardiac muscle, where all the muscle cells are electrically connected, an action potential is transmitted to the entire heart from a single loci of action potential generation. In addition, the chemical aspects of activation of skeletal muscle is somewhat different from those of cardiac muscle.
xe2x80x9cMuscle Recruitment with Infrafascicular Electrodesxe2x80x9d, by Nicola Nannini and Kenneth Horch, IEEE Transactions on Biomedical Engineering, Vol. 38, No. 8, pp. 769-776, August 1991, the disclosure of which is incorporated herein by reference, describes a method of varying the contractile force of skeletal muscles, by xe2x80x9crecruitingxe2x80x9d a varying number of muscle fibers. In recruiting, the contractile force of a muscle is determined by the number of muscle fibers which are activated by a stimulus.
However, it is generally accepted that cardiac muscle fibers function as a syncytium such that each and every cell contracts at each beat. Thus, there are no cardiac muscles fibers available for recruitment. See for example, xe2x80x9cExcitation Contraction Coupling and Cardiac Contractile Forcexe2x80x9d, by Donald M. Bers, Chapter 2, page 17, Kluwer Academic, 1991, the disclosure of which is incorporated herein by reference. This citation also states that in cardiac muscle cells, contractile force is varied in large part by changes in peak calcium.
xe2x80x9cEffect of Field Stimulation on Cellular Repolarization in Rabbit Myocardiumxe2x80x9d, by Stephen B. Knisley, William M. Smith and Raymond E. Ideker, Circulation Research, Vol. 70, No. 4, pp. 707-715, April 1992, the disclosure of which is incorporated herein by reference, describes the effect of an electrical field on rabbit myocardium. In particular, this article describes prolongation of an action potential as a result of a defibrillation shock and ways by which this effect can cause defibrillation to fail. One hypothesis is that defibrillation affects cardiac cells by exciting certain cells which are relatively less refractory than others and causes the excited cells to generate a new action potential, effectively increasing the depolarization time.
xe2x80x9cOptical Recording in the Rabbit Heart Show That Defibrillation Strength Shocks Prolong the Duration of Depolarization and the Refractory Periodxe2x80x9d, by Stephen M. Dillon, Circulation Research, Vol. 69, No. 3, pp. 842-856, September, 1991, the disclosure of which is incorporated herein by reference, explains the effect of prolonged repolarization as caused by the generation of a new action potential in what was thought to be refractory tissue as a result of the defibrillation shock. This article also proves experimentally that such an electric shock does not damage the cardiac muscle tissue and that the effect of a second action potential is not due to recruitment of previously unactivated muscle fibers. It is hypothesized in this article that the shocks hyperpolarize portions of the cellular membrane and thus reactivate the sodium channels. In the experiments described in this article, the activity of calcium channels is blocked by the application of methoxy-verapamil.
xe2x80x9cElectrical Resistances of Interstitial and Microvascular Space as Determinants of the Extracellular Electrical field and Velocity of Propagation in Ventricular Myocardiumxe2x80x9d, by Johannes Fleischhauer, Lilly Lehmann and Andre G. Kleber, Circulation, Vol. 92, No. 3, pp. 587-594, Aug. 1, 1995, the disclosure of which is incorporated herein by reference, describes electrical conduction characteristics of cardiac muscle.
xe2x80x9cInhomogeneity of Cellular Activation Time and Vmax in Normal Myocardial Tissue Under Electrical Field Stimulationxe2x80x9d, by Akihiko Taniguchi, Junji Toyama, Itsuo Kodama, Takafumi Anno, Masaki Shirakawa and Shiro Usui, American Journal of Physiology, Vol. 267 (Heart Circulation Physiology, Vol. 36), pp. H694-H705, 1994, the disclosure of which is incorporated herein by reference, describes various interactions between electro-tonic currents and action potential upstrokes.
xe2x80x9cEffect of Light on Calcium Transport in Bull Sperm Cellsxe2x80x9d, by R. Lubart, H. Friedmann, T. Levinshal, R. Lavie and H. Breitbart, Journal of Photochemical Photobiology B, Vol. 14, No. 4, pp. 337-341, Sep. 12, 1992, the disclosure of which is incorporated herein by reference, describes an effect of light on bull sperm cells, in which laser light increases the calcium transport in these cells. It is also known that low level laser light affects calcium transport in other types of cells, for example as described in U.S. Pat. No. 5,464,436, the disclosure of which is incorporated herein by reference.
The ability of electro-magnetic radiation to affect calcium transport in cardiac myocytes is well documented. Loginov V A, xe2x80x9cAccumulation of Calcium Ions in Myocardial Sarcoplasmic Reticulum of Restrained Rats Exposed to the Pulsed Electromagnetic Fieldxe2x80x9d, in Aviakosm Ekolog Med, Vol. 26, No. 2, pp. 49-51, March-April, 1992, the disclosure of which is incorporated herein by reference, describes an experiment in which rats were exposed to a 1 Hz field of between 6 and 24 mTesla After one month, a reduction of 33 percent in the velocity of calcium accumulation was observed. After a second month, the accumulation velocity was back to normal, probably due to an adaptation mechanism.
Schwartz J L, House D E and Mealing G A, in xe2x80x9cExposure of Frog Hearts to CW or Amplitude-Modulated VHF Fields: Selective Efflux of Calcium Ions at 16 Hzxe2x80x9d, Bioelectromagnetics, Vol. 11, No. 4, pp. 349-358, 1990, the disclosure of which is incorporated herein by reference, describes an experiment in which the efflux of calcium ions in isolated frog hearts was increased by between 18 and 21% by the application of a 16 Hz modulated VHF electromagnetic field.
Lindstrom E, Lindstrom P, Berglund A, Lundgren E and Mild K H, in xe2x80x9cIntracellular Calcium Oscillations in a T-cell Line After Exposure to Extremely-Low-Frequency Magnetic Fields with Variable Frequencies and Flux Densitiesxe2x80x9d, Bioelectromagnetics, Vol. 16, No. 1, pp. 41-47, 1995, the disclosure of which is incorporated herein by reference, describes an experiment in which magnetic fields, at frequency between 5 and 100 Hz (Peak at 50 Hz) and with intensities of between 0.04 and 0.15 mTesla affected calcium ion transport in T-cells.
Loginov V A, Gorbatenkova N V and Klimovitskii Vla, in xe2x80x9cEffects of an Impulse Electromagnetic Field on Calcium Ion Accumulation in the Sarcoplasmatic Reticulum of the Rat Myocardiumxe2x80x9d, Kosm Biol Aviakosm Med, Vol. 25, No. 5, pp. 51-53, September-October, 1991, the disclosure of which is incorporated herein by reference, describes an experiment in which a 100 minute exposure to a 1 msec impulse, 10 Hz frequency and 1-10 mTesla field produced a 70% inhibition of calcium transfer across the sarcoplasmic reticulum. The effect is hypothesized to be associated with direct inhibition of Ca-ATPasec.
It should be noted that some researchers claim that low frequency magnetic fields do NOT have the above reported effects. For example, Coulton L A and Barker A T, in xe2x80x9cMagnetic Fields and Intracellular Calcium: Effects on Lymphocytes Exposed to Conditions for xe2x80x98Cyclotron Resonancexe2x80x99xe2x80x9d, Phys Med Biol, Vol. 38, No. 3, pp. 347-360, March, 1993, the disclosure of which is incorporated herein by references, exposed lymphocytes to radiation at 16 and 50 Hz, for a duration of 60 minutes and failed to detect any changes in calcium concentration.
Pumir A, Plaza F and Krinsky V I, in xe2x80x9cControl of Rotating Waves in Cardiac Muscle: Analysis of the Effect of Electric Fieldsxe2x80x9d, Proc R Soc Lond B Biol Sci, Vol. 257, No. 1349, pp. 129-34, Aug. 22, 1994, the disclosure of which is incorporated herein by reference, describes that an application of an external electric field to cardiac muscle affects conduction velocity by a few percent. This effect is due to the hyperpolarization of one end of muscle cells and a depolarization of the other end of the cell. In particular, an externally applied electric field favors propagation antiparallel to it. It is suggested in the article to use this effect on conduction velocity to treat arrhythmias by urging rotating waves, which are the precursors to arrhythmias, to drift sideways to non-excitable tissue and die.
xe2x80x9cControl of Muscle Contractile Force Through Indirect High-Frequency Stimulationxe2x80x9d, by M. Sblomonow, E. Eldred, J. Lyman and J. Foster, American Journal of Physical Medicine, Vol. 62, No. 2, pp. 71-82, April 1983, the disclosure of which is incorporated herein by reference, describes a method of controlling skeletal muscle contraction by varying various parameters of a 500 Hz pulse of electrical stimulation to the muscle.
xe2x80x9cBiomedical Engineering Handbookxe2x80x9d, ed. Joseph D. Bronzino, chapter 82.4, page 1288, IEEE press/CRC press, 1995, describes the use of precisely timed subthreshold stimuli, simultaneous stimulation at multiple sites and pacing with elevated energies at the site of a tachycardia foci, to prevent tachycardia. However, none of these methods had proven practical at the time the book was written. In addition a biphasic defibrillation scheme is described and it is theorized that biphasic defibrillation schemes are more effective by virtue of a larger voltage change when the phase changes or by the biphasic waveform causing hyperpolarization of tissue and reactivation of sodium channels.
xe2x80x9cSubthreshold Conditioning Stimuli Prolong Human Ventricular Refractorinessxe2x80x9d, Windle J R, Miles W M, Zipes D P and Prystowsky E N, American Journal of Cardiology, Vol. 57, No. 6, pp 381-386, February, 1986, the disclosure of which is incorporated herein by reference, describes a study in which subthreshold stimuli were applied before a premature stimulus and effectively blocked the premature stimulus from having a pro-arrhythmic effect by a mechanism of increasing the refractory period of right ventricular heart tissue.
xe2x80x9cUltrarapid Subthreshold Stimulation for Termination of Atrioventricular Node Reentrant Tachycardiaxe2x80x9d, Fromer M and Shenasa M, Journal of the American Collage of Cardiology, Vol. 20, No. 4, pp. 879-883, October, 1992, the disclosure of which is incorporated herein by reference, describes a study in which trains of subthreshold stimuli were applied asynchronously to an area near a reentry circuit and thereby terminated the arrhythmia. Subthreshold stimuli were described as having both an inhibitory and a facilitating effect on conduction. In addition, subthreshold stimuli are described as reducing the threshold of excitability, possibly even causing an action potential.
xe2x80x9cInhibition of Premature Ventricular Extrastimuli by Subthreshold Conditioning Stimulixe2x80x9d, Skale B, Kallok M J, Prystowsky E N, Gill R M and Zipes D P, Journal of the American Collage of Cardiology, Vol. 6, No. 1, pp. 133-140, July, 1985, the disclosure of which is incorporated herein by reference, describes an animal study in which a train of 1 msec duration pulses were applied to a ventricle 2 msec before a premature stimuli, inhibited the response to the premature stimuli, with a high frequency train delaying the response for a much longer amount of time (152 msec) than a single pulse (20 msec). The delay between the pacing of the ventricle and the pulse train was 75 msec. However, the subthreshold stimuli only had this effect when delivered to the same site as the premature stimulus. It is suggested to use a subthreshold stimuli in to prevent or terminate tachycardias, however, it is noted that this suggestion is restrained by the spatial limitation of the technique.
xe2x80x9cThe Phase of Supernormal Excitation in Relation to the Strength of Subthreshold Stimulixe2x80x9d, Yokoyama M, Japanese Heart Journal, Vol. 17, No. 3, pp. 35-325, May, 1976, the disclosure of which is incorporated herein by reference, describes the effect of varying the amplitude of a subthreshold stimuli on supernormal excitation. When the amplitude of the stimuli was increased, the supernormal excitation phase increased in length.
It is an object of some aspects of the present invention to provide a method of locally controlling the electrical and/or mechanical activity of cardiac muscle cells, in situ. Preferably, continuous control is applied. Alternatively, discrete control is applied. Further preferably, the control may be varied between cardiac cycles. One example of electrical control is shortening the refractory period of a muscle fiber by applying a negative voltage to the outside of the cell. The cell may also be totally blocked from reacting by maintaining a sufficiently positive voltage to the outside of the cell, so that an activation signal fails to sufficiently depolarize the cellular membrane. One example of mechanical control includes increasing or decreasing the strength of contraction and the duration of the contraction. This may be achieved by extending or shortening the plateau and/or the action potential duration by applying non-excitatory voltage potentials across the cell. The increase in strength of contraction may include an increase in peak force of contraction attained by muscle fibers, may be an increase in an average force of contraction, by synchronization of contraction of individual fibers or may include changing the timing of the peak strength.
It should be appreciated that some aspects of the present invention are different from both pacemaker operation and defibrillator operation. A pacemaker exerts excitatory electric fields for many cycles, while a defibrillator does not repeat its applied electric field for many cycles, due to the disruptive effect of the defibrillation current on cardiac contraction. In fact, the main effect of the defibrillation current is to reset the synchronization of the heart by forcing a significant percentage of the cardiac tissue into a refractory state. Also, defibrillation currents are several orders of magnitude stronger than pacing currents. It is a particular aspect of some embodiments of the present invention that the regular activation of the heart is not disrupted, rather, the activation of the heart is controlled, over a substantial number of cycles, by varying parameters of the reactivity of segments of cardiac muscle cells.
In some aspects of the invention, where the heart is artificially paced in addition to being controlled in accordance with the present invention, the activation cycle of the heart is normal with respect to the pacing. For example, when the control is applied locally, such that the activation of the rest of the heart is not affected.
In some aspect of the invention, the control is initiated as a response to an unusual cardiac event, such as the onset of fibrillation or the onset of various types of arrhythmias. However, in other aspects of the present invention, the control is initiated in response to a desired increase in cardiac output or other long-term effects, such as reducing the probability of ventricular fibrillation (VF) or increasing the coronary blood flow.
Another difference between defibrillation, pacing and some embodiments of the present invention is that defibrillation and pacing are applied as techniques to affect the entire heart (or at least an entire chamber), while certain embodiments of the present invention, for example, fences (described below), are applied to local portion of the heart (which may be as large as an entire chamber) with the aim of affecting only local activity. Yet another difference between some embodiment of the present invention and defibrillation is in the energy applied to the heart muscle. In defibrillation, a typical electric field strength is 0.5 Joule (which is believed to be strong enough to excite refractory tissue, xe2x80x9cOptical Recordings . . . xe2x80x9d, cited above), while in various embodiment of the invention, the applied field strength is between 50 and 500 micro joules, a field strength which is believed to not cause action potentials in refractory tissue.
It is a further object of some aspects of the present invention to provide a complete control system for the heart which includes, inter alia, controlling the pacing rate, refractory period, conduction velocity and mechanical force of the heart. Except for heart rate, each of these parameters may be locally controlled, i.e., each parameter will be controlled in only a segment of cardiac muscle. It should be noted that heart rate may also be locally controlled, especially with the use of fences which isolate various heart segments from one another, however, in most cases this is detrimental to the heart""s pumping efficiency.
In one preferred embodiment of the present invention, electrical and/or mechanical activity of a segment of cardiac muscle is controlled by applying a non-exciting field (voltage) or current across the segment. A non-exciting signal may cause an existing action potential to change, but it will not cause a propagating action potential, such as those induced by pacemakers. The changes in the action potential may include extension of the plateau duration, extension of the refractory period, shortening of the post-plateau repolariation and other changes in the morphology of the action potential. However, the nonexciting signal may affect a later action potential, for example, it may delay such a potential or may accelerate its onset. Another type of non-exciting signal is a voltage which does not cause a new contraction of the cardiac muscle cell to which the non-exciting signal is applied. Activation potential generation may be averted either by applying voltage of the wrong polarity; the voltage being applied when the cell and/or the surrounding cells are not sensitive to it or by the amplitude of the voltage being too small to depolarize the cell to the extent that a new action potential will be generated during that period.
Optionally, this control is exerted in combination with a pacemaker which applies an exciting signal to the heart. In a preferred embodiment of the invention, a pacemaker (or a defibrillator) incorporates a controller, operating in accordance with at least one embodiment of the invention. A pacemaker and a controller may share a battery, a micro-controller, sensors and possibly electrodes.
In another preferred embodiment of the present invention, arrhythmias and fibrillation are treated using fences. Fences are segments of cardiac muscle which are temporarily inactivated using electrical fields. In one example, atrial fibrillation is treated by channeling the activation signal from an SA node to an AV node by fencing it in. In another example, fibrillations are damped by fencing in the multitude of incorrect activation signals, so that only one path of activation is conducting. In still another example, ventricular tachycardia or fibrillation is treated by dividing the heart into insulated segments, using electrical fields and deactivating the fences in sequence with a normal activation sequence of the heart, so that at most only one segment of the heart will be prematurely activated.
In still another preferred embodiment of the invention, the muscle mass of the heart is redistributed using electrical fields. In general, changing the workload on a segment of cardiac muscle activates adaptation mechanisms which tend to change the muscle mass of the segment with time. Changing the workload may be achieved, in accordance with a preferred embodiment of the invention, by increasing or decreasing the action potential plateau duration of the segment, using applied electrical fields. Alternatively or additionally, the workload may be changed indirectly, in accordance with a preferred embodiment of the invention, by changing the activation time of the segment of the heart and/or its activation sequence. Further additionally or alternatively, the workload may be changed by directly controlling the contractility of a segment of the heart.
In yet another preferred embodiment of the invention, the operation of the cardiac pump is optimized by changing the activation sequence of the heart and/or by changing plateau duration at segments of the heart and/or by changing the contractility thereat.
In still another preferred embodiment of the invention, the cardiac output is modified, preferably increased, by applying a non-excitatory electric field to a segment of the heart, preferably the left ventricle. Preferably, the extent of increase in cardiac output, especially the left ventricular output, is controlled by varying the size of the segment of the heart to which such a field is applied. Alternatively or additionally, the strength of the electric field is changed. Alternatively or additionally, the timing of the pulse is changed. Alternatively or additionally, the duration, shape or frequency of the pulse is changed. The increase in output may include an increase in peak flow rate, in flow volume, in average flow rate, or it may include a change in the flow profile, such as a shift in the development of the peak flow, which improves overall availability of blood to body organs.
In still another preferred embodiment of the invention, the developed ventricular pressure is modified, preferably increased, by applying a non-excitatory electric field to a segment of the heart, preferably the left ventricle. Preferably, the extent of increase in cardiac output is controlled by varying the size of the segment of the heart to which such a field is applied. Alternatively or additionally, the strength of the electric field is changed. Alternatively or additionally, the timing of the pulse is changed. Alternatively or additionally, the duration of the pulse is changed. Alternatively or additionally, the waveform of the pulse is changed. Alternatively or additionally, the frequency of the pulse is changed. The increase in pressure may include an increase in peak pressure, average pressure or it may include a change in the pressure profile, such as a shift in the development of the peak pressure, which improves the contractility.
In accordance with yet another preferred embodiment of the invention, the afterload of the heart is increased by applying non-excitatory electric fields to at least a segment of the heart, whereby the flow in the coronary arteries is improved.
In accordance with another preferred embodiment of the invention various cardiac parameters are controlled via inherent cardiac feedback mechanisms. In one example, the heart rate is controlled by applying a non-exciting voltage to pacemaker cells of the heart, at or near the SA node of the heart. Preferably, the heart rate is increased by applying the non-excitatory field.
In a preferred embodiment of the invention, a single field is applied to a large segment of the heart. Preferably, the field is applied at a time delay after the beginning of the systole. Preferably, the non-exciting field is stopped before half of the systole is over, to reduce the chances of fibrillation.
In another preferred embodiment of the invention, a plurality of segments of the heart are controlled, each with a different non-excitatory electric field. Preferably, each electric field is synchronized to the local activation or other local parameters, such as initiation of contraction. A further preferred embodiment of the invention takes into account the structure of the heart. The heart muscle is usually disposed in layers, with each layer having a (different) muscle fiber orientation. In this embodiment of the invention, a different field orientation and/or polarity is preferably applied for different orientations of muscle fibers.
In one preferred embodiment of the invention, this technique, which takes the muscle fiber orientation into account, may be applied to local defibrillation-causing electric fields. the purpose of which fields may be to delay the repolarization of a certain, limited segment of the heart, thereby creating a fence.
There is therefore provided in accordance with a preferred embodiment of the invention, a method of modifying the force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, which causes the force of contraction to be increased by at least 5%.
Preferably, the force is increased by a greater percentage such as at least 10%, 30% or 50%.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, to the portion at a delay of less than 70 msec after the activation.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, which causes the pressure in the chamber to be increased by at least 2%.
Preferably the pressure is increased by a greater amount such as at least 10% or 20%.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, wherein the chamber has a flow volume and wherein the flow volume is increased by at least 5%.
Preferably, the flow volume is increased by a greater amount such as at least 10% or 20%.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the force of contraction of at least a portion of a heart chamber. comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, wherein the chamber has a flow rate such that the flow rate is increased by at least 5%.
Preferably, the flow rate is increased by a greater amount such as at least 10% or 20%.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field to the portion at a delay after the activation, the field having a given duration of at least 101 msec and not lasting longer than the cycle length. Preferably the duration is longer, such as at least 120 msec or 150 msec.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the portion of the chamber has an inner surface and an outer surface and wherein the field is applied between the inner surface and the outer surface.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the portion of the chamber has an inner surface and an outer surface and wherein the field is applied along the outer surface.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the portion of the chamber has an inside surface, an outside surface and an intra-muscle portion and wherein the field is applied between the intra-muscle portion and at least one of the surfaces.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the field is applied between a single electrode and a casing of an implanted device.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, using an electrode floating inside the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the field is applied using at least two electrodes and wherein the at least two electrodes are at least 2 cm apart.
In preferred embodiments of the invention the electrodes are at least 4 or 9 cm apart.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the field is applied using at least two electrodes and wherein one electrode of the at least two electrodes is at a base of a chamber of the heart and one electrode is at an apex of a chamber of the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the field is applied using at least three electrodes and wherein applying a non-excitatory field comprises:
electrifying a first pair of the at least three electrodes; and
subsequently electrifying a second pair of the at least three electrodes.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, wherein the field is applied using at least two electrodes placed externally to the subject.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion,
wherein the electric field at least partially cancels electro-tonic currents in at least the portion of the heart chamber.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion between two positions; and
sensing an activation at a site between the two positions.
There is further provided in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion between two positions; and
sensing an activation at a site coinciding with one of the two positions.
There is further provided in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion between two positions;
sensing an activation at a site; and
estimating the activation of the portion from the sensed activation.
Preferably sensing comprises sensing a value of a parameter of an ECG and wherein estimating comprises estimating the delay based on a delay value associated with the value of the parameter.
Preferably, the site is at a different chamber of the heart than the chamber at which the field is applied.
Preferably, the site is substantially the earliest activated site in the chamber of the portion.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion; and
applying a second non-excitatory electric field to a second portion of the chamber.
There is further provided, in accordance with a preferred embodiment of the invention a method according to claim 36, wherein the second field is applied in the same cardiac cycle as the non-excitatory field.
Preferably, each portion has an individual activation to which the applications of the field thereat are synchronized.
Preferably, the second field has a different effect on the heart than the non-excitatory field.
Preferably, only the second non-excitatory field is applied during a different cardiac cycle.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
estimating the activation at the portion; and
applying a non-excitatory electric field having a given duration, at a delay after the estimated activation, to the portion.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion; and
repeating application of the non-excitatory field, during a plurality of later heart beats, at least some of which are not consecutive.
Preferably, the method comprises gradually reducing the frequency at which beats are skipped during the repeated application.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
applying a non-excitatory electric field having a given duration, at a delay after the activation, to the portion, wherein the portion has an extent; and
changing the extent of the portion to which the field is applied, between beats.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
irradiating the portion with light synched to the activation; and
repeating irradiating at at least 100 cardiac cycles, during a period of less than 1000 cardiac cycles.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation;
irradiating the portion with radio frequency radiation synched to the activation; and
repeating irradiating at at least 100 cardiac cycles, during a period of less than 1000 cardiac cycles.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
modifying the availability of calcium ions inside muscle fibers of the portion, during a period of time including a time less than 70 msec after the activation, in response to the activation.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
modifying the transport rate of calcium ions inside muscle fibers of the portion, during a period of time less than 70 msec after the activation, in response to the activation.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying a force of contraction of at least a portion of a heart chamber, comprising:
providing a subject having a heart, comprising at least a portion having an activation; and
modifying the availability of catecholamines at the portion in synchrony with the activation.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the activation profile of at least a portion of a heart, comprising,
mapping the activation profile of the portion;
determining a desired change in the activation profile; and
modifying, using a non-excitatory electric field, the conduction velocity in a non-arrhythmic segment of the portion, to achieve the desired change.
In a preferred embodiment of the invention, wherein the desired change is an AV interval and wherein modifying comprises modifying the conduction velocities of purkinje fibers between an AV node and at least one of the ventricles in the heart.
In a preferred embodiment of the invention, the activation comprises an average activation of the portion.
In a preferred embodiment of the invention, the activation comprises an earliest activation.
In a preferred embodiment of the invention, the activation comprises a mechanical activation.
In a preferred embodiment of the invention, wherein the activation comprises an electrical activation.
In a preferred embodiment of the invention, wherein the portion comprises a plurality of subportions, each having an individual activation and wherein applying a field comprises applying a field to each subportion at a delay relative to the individual activation of the subportion.
In a preferred embodiment of the invention, applying a non-excitatory electric field comprises driving an electric current through the segment. Preferably, the current is less than 20 mA. In some embodiments of the invention the current is less than 8 mA, 5 mA, 3 mA. Preferably, the current is at least 0.5 mA. In some embodiments it is at least 1 or 3 mA.
In a preferred embodiment of the invention, the field is applied for a duration of between 10 and 140 msec. In other preferred embodiments it is applied for between 20 and 100 msec, or 60 and 90 msec.
In a preferred embodiment of the invention, the delay is less than 70 msec. In other preferred embodiments it is less than 40, 20, 5 or 1 msec. In some embodiments the delay is substantially equal to zero.
In a preferred embodiment of the invention, the delay is at least 1 msec. In other preferred embodiments it may be more than 3, 7, 15 or 30 msec.
In a preferred embodiment of the invention, the electric field has an exponential temporal envelope. In others it has a square, triangular, ramped or biphasic temporal envelope. Preferably the electric field comprises an AC electric field, preferably having a sinusoidal, saw tooth or square wave temporal envelope.
In a preferred embodiment of the invention, wherein the portion of the chamber has an inside surface and an outside surface, wherein the field is applied along the inner surface.
In a preferred embodiment of the invention, wherein the portion of the chamber has a normal conduction direction, wherein the field is applied along the normal conduction direction.
In a preferred embodiment of the invention, wherein the portion of the chamber has a normal conduction directions wherein the field is applied perpendicular to the normal conduction direction.
In a preferred embodiment of the invention, the field is applied between at least two electrodes. Preferably, the electrodes are at least 2 cm apart. In some preferred embodiments the electrodes are at least 4 or 9 cm apart.
The chamber may be any of the left ventricle, the left atrium, the right ventricle or the right atrium.
A preferred embodiment of the invention includes pacing the heart. Preferably, applying the electric field is synchronized with the pacing.
In a preferred embodiment of the invention, the method includes calculating the delay based on the pacing.
In a preferred embodiment of the invention, the method includes sensing a specific activation at a site.
There is further provided, in accordance with a preferred embodiment of the invention, a method of modifying the activation profile of at least a portion of a heart, comprising,
mapping the activation profile of the portion;
determining a desired change in the activation profile; and
blocking the activation of at least a segment of the portion, to achieve the desired change, wherein the segment is not part of a reentry circuit or an arrhythmia foci in the heart.
In a preferred embodiment of the invention, the blocked segment is an ischemic segment.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the activation profile of at least a portion of a heart, comprising,
mapping the activation profile of the portion;
determining a desired change in the activation profile; and
changing the refractory period of at least a segment of the portion, to achieve the desired change, wherein the segment is not part of a reentry circuit or an arrhythmia foci in the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying the heart rate of a heart, comprising:
providing a subject having a heart with an active natural pacemaker region; and
applying a non-excitatory electric field to the region.
Preferably, the electric field extends a duration of an action potential of the region.
Preferably the method comprises extending the refractory period of a significant portion of the right atrium.
There is further provided, in accordance with a preferred embodiment of the invention a method of reducing an output of a chamber of a heart, comprising:
determining the earliest activation of at least a portion of the chamber, which portion is not part of an abnormal conduction pathway in the heart; and
applying a non-excitatory electric field to the portion.
Preferably, the field is applied prior to activation of the portion.
Preferably, the field reduces the reactivity of the portion to an activation signal.
Preferably, the field reduces the sensitivity of the portion to an activation signal.
There is further provided, in accordance with a preferred embodiment of the invention a method of reducing an output of a chamber of a heart, comprising:
determining an activation of and conduction pathways to at least a portion of the chamber; and
reversibly blocking the conduction pathways, using a locally applied non-excitatory electric field.
There is further provided, in accordance with a preferred embodiment of the invention a method of reducing an output of a chamber of a heart, comprising:
determining an activation of and a conduction pathway to at least a portion of the chamber, which portion is not part of an abnormal conduction pathway in the heart; and
reversibly reducing the conduction velocity in the conduction pathway, using a locally applied electric field.
There is further provided, in accordance with a preferred embodiment of the invention a method of performing cardiac surgery, comprising:
blocking the electrical activity to at least a portion of the heart using a non-excitatory electric field; and
performing a surgical procedure on the portion.
There is further provided, in accordance with a preferred embodiment of the invention a method of performing cardiac surgery, comprising:
reducing the sensitivity to an activation signal of at least a portion of the heart using a non-excitatory electric field; and
performing a surgical procedure on the portion.
There is ether provided in accordance with a preferred embodiment of the invention a method of controlling the heart, comprising,
providing a subject having a heart with a left ventricle and a right ventricle;
selectively reversibly increasing the contractility of one of the ventricles relative to the other ventricle.
Preferably, selectively reversibly increasing comprises applying a non-excitatory electric field to at least a portion of the one ventricle.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling the heart, comprising,
providing a subject having a heart with a left ventricle and a right ventricle;
selectively reversibly reducing the contractility of one of the ventricles, relative to the other ventricle.
Preferably, selectively reversibly reducing comprises applying a non-excitatory electric field to at least a portion of the one ventricle.
There is further provided, in accordance with a preferred embodiment of the invention a method of treating a segment of a heart which is induces arrhythmias due to an abnormally low excitation threshold, comprising:
identifying the segment; and
applying a desensitizing electric field to the segment, such that the excitation threshold is increased to a normal range of values.
There is further provided, in accordance with a preferred embodiment of the invention a method of modifying an activation profile of at least a portion of a heart, comprising:
determining a desired change in the activation profile; and
reversibly blocking the conduction of activation signals across a plurality of elongated fence portions of the heart to achieve the desired change.
Preferably, blocking the conduction creates a plurality of segments, isolated from external activation, in the portion of the heart. Preferably, at least one of the isolated segments contains an arrhythmia foci. Preferably, at least one of the isolated segments does not contain an arrhythmia foci.
Preferably, the method includes individually pacing each of at least two of the plurality of isolated segments.
Preferably, blocking the conduction limits an activation front from traveling along abnormal pathways.
Preferably, reversibly blocking comprises reversibly blocking conduction of activation signals, synchronized with a cardiac cycle, to block abnormal activation signals.
In a preferred embodiment of the invention reversibly blocking comprises reversibly blocking conduction of activation signals, synchronized with a cardiac cycle, to pass normal activation signals.
There is further provided, in accordance with a preferred embodiment of the invention a method of treating abnormal activation of the heart, comprising:
detecting an abnormal activation state; and
modifying the activation of the heart in accordance with the above described method to stop the abnormal activation condition.
In a preferred embodiment of the invention the abnormal condition is fibrillation.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling the heart comprising:
determining a desired range of values for at least one parameter of cardiac activity; and
controlling at least a local force of contraction in the heart to maintain the parameter within the desired range.
Preferably, controlling includes controlling the heart rate.
Preferably, controlling includes controlling a local conduction velocity.
Preferably, the parameter responds to the control with a time constant of less than 10 minutes. Alternatively it responds with a time constant of more than a day.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling the heart, comprising:
determining a desired range of values for at least one parameter of cardiac activity;
controlling at least a portion of the heart using a non-excitatory electric field having at least one characteristic, to maintain the parameter within the desired range; and
changing the at least one characteristic in response to a reduction in a reaction of the heart to the electric field.
Preferably, the characteristic is a strength of the electric field. Alternatively it comprises a duration of the electric field, a frequency of the field or a wave form of the field.
There is further provided, in accordance with a preferred embodiment of the invention a method of treating a patient having a heart with an unhealed infarct, comprising, applying any of the above methods, until the infarct is healed.
There is further provided, in accordance with a preferred embodiment of the invention a method of treating a patient having a heart, comprising,
providing a patient, having an unhealed infarct in the heart; and
applying one of the above methods until the heart is stabilized.
In a preferred embodiment of the invention applying a non-excitatory field comprises applying a non-excitatory field for between 3 and 5000 heart beats.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration at least 100 times during a period of less than 50,000 cardiac cycles.
Preferably, are electrified at least 1000 times during a period of less than 50,000 cardiac cycles. They may also be electrified at least 1000 times during a period of less than 20,000 cardiac cycles or at least 1000 times during a period of less than 5,000 cardiac cycles.
Preferably, the field is applied less than 10 times in one second.
In a preferred embodiment of the invention, the power supply electrifies the electrodes at least 2000 times over the period. In preferred embodiments the power supply electrifies the electrodes at least 4000 times over the period.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration,
wherein at least one of the electrodes is adapted to cover an area of the heart larger than 2 cm2.
Preferably at least one of the electrodes is adapted to cover an area of the heart larger than 6 or 9 cm2.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
at least one unipolar electrode adapted to apply an electric field to at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field.
Preferably the apparatus comprises a housing, which is electrified as a second electrode.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration,
wherein the distance between the electrodes is at least 2 cm.
In preferred embodiments of the invention the distance is at least 4 or 9 cm.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
at least three electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration,
wherein the electrodes are selectively electrifiable in at least a first configuration where two electrodes are electrified and in a second configuration where two electrodes, not both identical with the first configuration electrodes, are electrified.
There is further provided in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart;
a sensor which senses a local activation; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration, responsive to the sensed local activation.
Preferably the sensor senses a mechanical activity of the portion.
Preferably, the sensor is adapted to sense the activation at at least one of the electrodes.
Preferably, the sensor is adapted to sense the activation in the right atrium.
Preferably, the sensor is adapted to sense the activation between the electrodes.
Preferably, the sensor senses an earliest activation in a chamber of the heart including the portion and wherein the power supply times the electrification responsive to the earliest activation.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
electrodes adapted to apply an electric field across elongate segments of at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field.
Preferably, the electrodes are elongate electrodes at least one cm long. In other embodiments they are at least 2 or 4 cm long. Preferably the segments are less than 0.3 cm wide. In some embodiments they are less than 0.5, 1 or 2 cm wide.
Preferably, the power supply electrifies the electrodes for a given duration of at least 20 msec, at least 1000 times over a period of less than 5000 cardiac cycles.
In preferred embodiments of the invention, the elongate segments divide the heart into at least two electrically isolated segments in the heart.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart;
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration; and
a circuit for determining an activation at a site in the portion,
wherein the power supply electrifies the electrodes responsive to the determined activation.
Preferably, the electric field is applied at a given delay, preferably less than 70 msec, after an activation at one of the electrodes.
In a preferred embodiment of the invention the electric field is applied before an activation at one of the electrodes. In various preferred embodiments of the invention the field is applied more than 30, 50 or 80 msec before the activation.
Preferably, the circuit comprises an activation sensor which senses the activation. Alternatively or additionally the activation is calculated, preferably based on an activation in a chamber of the heart different from a chamber including the portion.
Preferably the apparatus includes a memory which stores values used to calculate a delay time, associated with a value of at least a parameter of a sensed ECG. Preferably, the parameter is a heart rate.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart;
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration;
a sensor which measures a parameter of cardiac activity; and
a controller which controls the electrification of the electrodes to maintain the parameter within a range of values.
The apparatus preferably comprises a memory which stores a map of electrical activity in the heart, wherein the controller uses the map to determine a desired electrification.
The apparatus preferably comprises a memory which stores a model of electrical activity in the heart, wherein the controller uses the model to determine a desired electrification.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart;
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration; and
a controller which measures a reaction of the heart to the electrification of the electrodes.
Preferably, the controller changes the electrification based on the measured reaction. Preferably, the apparatus includes a memory which stores the measured reaction.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart;
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration; and
a pacemaker which paces the heart.
Preferably, the pacemaker and the remainder of the apparatus are contained in a common housing.
Preferably, the pacemaker and the remainder of the apparatus utilize common excitation electrodes. Preferably, the pacemaker and the remainder of the apparatus utilize a common power supply.
Preferably, the non-excitatory field is synchronized to the pacemaker.
Preferably, the electrodes are electrified using a single pulse which combines a pacing electric field and a non-excitatory electric field.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration,
wherein at least one of the electrodes is mounted on a catheter.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for controlling a heart comprising:
a plurality of electrodes adapted to apply an electric field across at least a portion of the heart; and
a power supply which electrifies the electrodes with a non-excitatory electric field, for a given duration,
wherein the electrodes are adapted to be applied externally to the body.
Preferably, the apparatus includes an external pacemaker.
Preferably, the apparatus comprises an ECG sensor, to which electrification of the electrodes is synchronized.
In a preferred embodiment of the invention the duration of the field is at least 20 msec. In other preferred embodiments the duration is at least 40, 80 or 120.
In a preferred embodiment of the invention a current is forced through the portion. between the electrodes.
Preferably, the apparatus includes at least another two electrodes, electrified by the power supply and adapted to apply a non-excitatory electric field across a second portion of the heart. Preferably, the apparatus comprises a controller which coordinates the electrification of all the electrodes in the apparatus.
Preferably, a peak current through the electrodes is less than 20 mA. In some preferred embodiments it is less than 10, 5 or 2 mA.
In preferred embodiments of the invention the electrodes are adapted to be substantially in contact with the heart.
Preferably the electric field has an exponential, triangular or square wave shape. The field may be unipolar or bipolar. The field may have a constant strength.
There is further provided, in accordance with a preferred embodiment of the invention apparatus for optical control of a heart, comprising:
at least one implantable light source which generates pulses of light, for at least 1000 cardiac cycles, over a period of less than 5000 cycles; and
at least one wave guide for providing non-damaging intensities of light from the light source to at least one site on the heart.
Preferably, the at least one light source comprises a plurality of light sources, each attached to a different site on the heart.
Preferably, the wave guide is an optical fiber.
Preferably, the light source comprises a monochrome light source.
In a preferred embodiment of the invention the apparatus comprises a sensor, which measures an activation of at least portion of the heart, wherein the light source provides pulsed light in synchrony with the measured activation.
There is further provided, in accordance with a preferred embodiment of the invention a method of programming a programmable controller for a subject having a heart, comprising:
determining pulse parameters suitable for controlling the heart using non-excitatory electric fields; and
programming the controller with the pulse parameters.
Preferably, determining pulse parameters comprises determining a timing of the pulse relative to a cardiac activity.
Preferably, the cardiac activity is a local activation.
Preferably, determining a timing comprises determining timing which does not induce fibrillation in the heart.
Preferably, determining a timing comprises determining a timing which does not induce an arrhythmia in the heart.
Preferably, determining a timing comprises determining the timing based on a map of an activation profile of the heart.
Preferably, determining a timing comprises calculating a delay time relative to a sensed activation.
Preferably, controlling the heart comprises modifying the contractility of the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of determining an optimal placement of at least two individual electrodes for controlling a heart using non-excitatory electric fields, comprising:
determining an activation profile of at least a portion of the heart; and
determining an optimal placement of the electrodes in the portion based on the activation profile.
Preferably the method includes determining an optimal location for an activation sensor, relative to the placement of the electrodes.
Preferably, controlling comprises modifying the contractility.
Preferably, controlling comprises creating elongate non-conducting segments in the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of determining a timing parameter for a non-excitatory, repeatably applied pulse for a heart, comprising:
applying a non-excitatory pulse using a first delay;
determining if the pulse induces an abnormal activation profile in the heart; and
repeating applying a non-excitatory pulse using a second delay, shorter than the first, if the pulse did not induce abnormal activation in the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of determining a timing parameter for a non-excitatory, repeatably applied pulse for a heart, comprising:
applying a non-excitatory pulse using a first delay;
determining if the pulse induces an abnormal activation profile in the heart; and
repeating applying a non-excitatory pulse using a second delay, longer than the first, if the pulse did not induce abnormal activation in the heart.
There is further provided, in accordance with a preferred embodiment of the invention a method of programming a programmable controller for a heart, comprising:
controlling the heart using plurality of non-excitatory electric field sequences;
determining a response of the heart to each of the sequences; and
programming the controller responsive to the response of the heart to the non-excitatory sequences.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling an epileptic seizure, comprising:
detecting an epileptic seizure in brain tissue; and
applying a non-excitatory electric field to the brain tissue to attenuate conduction of a signal in the tissue.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling nervous signals in periphery nerves, comprising,
selecting a nerve; and
applying a non-excitatory electric field to the nerve to attenuate conduction of nervous signals in the nerve.
There is further provided, in accordance with a preferred embodiment of the invention a method of controlling a heart having a chamber comprising:
applying a non-excitatory electric field to a first portion of a chamber, such that a force of contraction of the first portion is lessened; and
applying a non-excitatory electric field to a second portion of a chamber, such that a force of contraction of the second portion is increased heart beat. Alternatively or additionally, the delay is at least 0.5 or 1 msec, optionally, 3 msec, optionally 7 msec and also optionally 30 msec.
There is further provided in accordance with a preferred embodiment of the invention, a method of controlling the heart including determining a desired range of values for at least one parameter of cardiac activity and controlling at least a local contractility and a local conduction velocity in the heart to maintain the parameter within the desired range.
Preferably, the parameter responds to the control with a time constant of less than 10 minutes, alternatively, the parameter responds to the control with a time constant of between 10 minutes and 6 hours, alternatively, with a time constant of between 6 hours and a day, alternatively, with a time constant between a day and a week, alternatively, a time constant of between a week and month, alternatively, a time constant of over a month.
There is also provided in accordance with a preferred embodiment of the invention, a method of controlling the heart, including determining a desired range of values for at least one parameter of cardiac activity, controlling at least a portion of the heart using a non-excitatory electric field having at least one characteristic, to maintain the parameter within the desired range and changing the at least one characteristic in response to a reduction in a reaction of the heart to the electric field. Preferably, the characteristic is the strength of the electric field. Alternatively or additionally, the characteristic is one or more of the duration of the electric field, its timing, wave form, and frequency.
In another preferred embodiment of the invention, the apparatus includes a sensor which measures a parameter of cardiac activity and a controller which controls the electrification of the electrodes to maintain the parameter within a range of values. Preferably, the apparatus includes a memory which stores a map of electrical activity in the heart, wherein the controller uses the map to determine a desired electrification. Alternatively or additionally, the apparatus includes a memory which stores a model of electrical activity in the heart, wherein the controller uses the model to determine a desired electrification.
There is also provided in accordance with a preferred embodiment of the invention, a method of controlling an epileptic seizure, including detecting an epileptic seizure in brain tissue and applying a non-excitatory electric field to the brain tissue to attenuate conduction of a signal in the tissue.